Heterogeneity in the Beta-Cell Population: a Guided Search Into Its Significance in Pancreas and in Implants

Pipeleers, Daniël; Mesmaeker, Ines De; Robert, Thomas; Hulle, Freya Van

doi:10.1007/s11892-017-0925-9

Cited by 28 publications

(20 citation statements)

References 68 publications

(118 reference statements)

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“…An outstanding issue is whether this long‐lasting hyperactivity reflects an adaptation of all β ‐cells or a recruitment of dormant β ‐cells or islets (Pipeleers et al. ). Anyhow, matching for donor BMI is important in in vitro studies of islet function.…”

Section: Discussionmentioning

confidence: 99%

Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets

Henquin¹

2018

Physiol Rep

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In vitro studies of human pancreatic islets are critical for understanding normal insulin secretion and its perturbations in diabetic β‐cells, but the influence of islet preparation characteristics and organ donor attributes in such experiments is poorly documented. Preparations from normal donors were tested with a standardized protocol evaluating dynamic insulin secretion induced by glucose, tolbutamide, and cAMP (forskolin). Secretion rates, normalized to insulin content (fractional insulin secretion), were analyzed as a function of preparation and donor characteristics. Low purity (25–45%) of the preparation (n = 8) blunted the first phase of insulin secretion induced by glucose or tolbutamide and increased basal secretion, resulting in threefold lower stimulation index than in more pure (55–95%) preparations (n = 43). In these more pure preparations, cold ischemia time (1–13 h) before pancreas digestion did not impact insulin secretion. Islet size (estimated by the islet size index) did not influence the dynamics of secretion, but fractional insulin secretion rates were greater in large than small islets, and positively correlated with islet size. Age of the donors (20–68 years) had no influence on islet size and insulin content or on dynamics and amplitude of insulin secretion, which were also similar in islets from male and female donors. In contrast, islet size and islet insulin content (normalized for size), and basal or stimulated insulin secretion positively correlated with Body‐Mass Index (19–33). These results contradict previous reports on the impact of donor age and islet size and point to possible confounding effects of donor BMI in insulin secretion studies with isolated human islets.

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Section: Discussionmentioning

confidence: 99%

Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets

Henquin¹

2018

Physiol Rep

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“…β-Cell heterogeneity has been suggested to arise during pancreatic development, to stem from differences or changes in islet architecture, or to result from β-cell replication or dedifferentiation (Roscioni et al, 2016). Very recently, several new studies have made important advances in our understanding of β-cell heterogeneity (Pipeleers et al, 2017), by identifying new markers [e.g. Flattop (Bader et al, 2016); CD9 and ST8SIA1 (Dorrell et al, 2016)] for a small subpopulation of β-cells that are more proliferative.…”

Section: Introductionmentioning

confidence: 99%

Evidence of a developmental origin of beta-cell heterogeneity using a dual lineage tracing technology

et al. 2019

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The Cre/loxP system has been used extensively in mouse models with a limitation of one lineage at a time. Differences in function and other properties among populations of adult β-cells is termed β-cell heterogeneity, which was recently associated with diabetic phenotypes. Nevertheless, the presence of a developmentally derived β-cell heterogeneity is unclear. Here, we have developed a novel dual lineage-tracing technology, using a combination of two recombinase systems, Dre/RoxP and Cre/LoxP, to independently trace green fluorescent Pdx1-lineage cells and red fluorescent Ptf1alineage cells in the developing and adult mouse pancreas. We detected a few Pdx1 + /Ptf1a − lineage cells in addition to the vast majority of Pdx1 + /Ptf1a + lineage cells in the pancreas. Moreover, Pdx1 + /Ptf1a + lineage β-cells had fewer Ki-67 + proliferating β-cells, and expressed higher mRNA levels of insulin, Glut2, Pdx1, MafA and Nkx6.1, but lower CCND1 and CDK4 levels, compared with Pdx1 + / Ptf1a − lineage β-cells. Furthermore, more TSQ-high, SSC-high cells were detected in the Pdx1 + Ptf1a + lineage population than in the Pdx1 + Ptf1a − lineage population. Together, these data suggest that differential activation of Ptf1a in the developing pancreas may correlate with this β-cell heterogeneity.

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“…We first revealed the presence of Vav1 expressing cells in the endocrine pancreas and, in particular, we found that insulin-producing cells express variable Vav1 levels. As β-cells are heterogeneous in their maturation levels, insulin secretion and specific phenotype [46,47], the presence of high levels of Vav1 in cells expressing low insulin and the low Vav1 staining in cells showing high insulin content suggest that Vav1 can be involved in the earlier stages of the maturation process of insulin producing-cells and/or that different levels of Vav1 identify different metabolic/subtypes of β-cells. Moreover, we found that ATRA induced a significant increase of Vav1 in the HPAF-2 cell line, a spontaneous variant of HPAF-I with a stem cell potential, able to undergo redifferentiation [11] or trans-differentiation to insulin producing cells [13] in response to the retinoid.…”

Section: Discussionmentioning

confidence: 99%

Vav1 Sustains the In Vitro Differentiation of Normal and Tumor Precursors to Insulin Producing Cells Induced by all-Trans Retinoic Acid (ATRA)

Brugnoli

Grassilli

Cardinale

et al. 2020

Stem Cell Rev and Rep

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All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells.

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Heterogeneity in the Beta-Cell Population: a Guided Search Into Its Significance in Pancreas and in Implants

Cited by 28 publications

References 68 publications

Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets

Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets

Evidence of a developmental origin of beta-cell heterogeneity using a dual lineage tracing technology

Vav1 Sustains the In Vitro Differentiation of Normal and Tumor Precursors to Insulin Producing Cells Induced by all-Trans Retinoic Acid (ATRA)

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